tbuckley/cabot-search huggingface dataset:
Abstract 3762: A novel lncRNA, <i>GTF2A1-AS1</i>, is required for cell cycle progression and cell proliferation
Authors: Yael Goldstein, Tali Nizri-Megnaji, Doron Ginsberg
Journal: Cancer Research (2023)

Abstract Long noncoding RNAs (lncRNAs) are major regulators of many cellular processes including cell cycle progression, cell proliferation and tumorigenesis. In this study, we identify a novel lncRNA, GTF2A1-AS1, and reveal its effects on cell cycle progression and cancer growth. Inhibition of GTF2A1-AS1 expression alters cell cycle distribution, leading to a decrease in the number of G1 cells and a concomitant increase in all other stages of the cell cycle, and in particular S phase, suggesting its involvement in the regulation of G1/S transition. Accordingly, knock down of GTF2A1-AS1 enhances G1 phase exit upon release from a late G1 block. In agreement with its suggested role in G1/S transition, prolonged silencing of GTF2A1-AS1 enhances proliferation of human cancer cells. GTF2A1-AS1 RNA is mostly nuclear and its gene is localized upstream to the protein-coding gene GTF2A1. GTF2A1-AS1 functions in trans to repress the expression of EIF5A2 and HOXA13. Knockdown of either EIF5A2 or HOXA13 rescues the effects of GTF2A1-AS1 silencing on cell proliferation, indicating that it functions mainly by modulating the levels of these two proteins. In agreement with the effect of GTF2A1-AS1 silencing on cell cycle progression and cell proliferation, low levels of GTF2A1-AS1 are associated with reduced survival in brain cancer patients. In conclusions, our data identify GTF2A1-AS1 as a novel lncRNA that regulates cell-cycle progression and cell proliferation and has a potential role in human cancer. Citation Format: Yael Goldstein, Tali Nizri-Megnaji, Doron Ginsberg. A novel lncRNA, GTF2A1-AS1, is required for cell cycle progression and cell proliferation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3762.
Abstract 1992: P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma
Authors: Daniel A. Heller, Daniel Tylawsky, G. Praveen Raju
Journal: Cancer Research (2023)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor with ~30% mediated by Sonic hedgehog (SHH) signaling. While SHH effector Smoothened inhibition is promising, therapeutic index is reduced by high systemic doses required for sufficient intracranial drug concentrations. Treatment-related toxicities associated with radiation therapy result in lifelong morbidity, and SHH pathway inhibition in children notably results in permanent bone defects. Here, we found that nanoparticle-mediated P-selectin targeting on tumor vasculature induces caveolin-1-dependent transcellular passage across the blood-brain barrier. A vismodegib nanocarrier that targets P-selectin exhibited striking efficacy and markedly reduced both bone-related toxicities and drug exposure to healthy brain. These findings demonstrate a potent strategy and novel mechanism for targeted intracranial pharmacodelivery that overcomes the restrictive endothelial barrier to achieve enhanced tumor-selective penetration and has therapeutic implications for other diseases within the central nervous system. Citation Format: Daniel A. Heller, Daniel Tylawsky, G. Praveen Raju. P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1992.
Abstract 1772: Development of a novel L1CAM-targeted CAR-T, CX804, and its therapeutic efficacy in ovarian and gastric cancer
Authors: Xiumei Che, Un-Jung Yun, Seokwon Lee, Youngyoub Kim, Junshub Lee, Jina Chae, Jehee Suh, Eun-Ji Nam, Gun Min Kim, Hyoyoung Kim, Minkyu Jung
Journal: Cancer Research (2023)

Abstract L1 cell adhesion molecule (L1CAM) is involved in cancer development and aberrantly expressed in various tumor. It is also associated with aggressive progression, metastasis, and poor prognosis. Public database, a Kaplan-Meier plotter (http://www.kmplot.com) shows that L1CAM high-expression significantly reduced survival of ovarian and gastric cancer patients. We developed a novel chimeric antigen receptor (CAR)-T cell targeted to L1CAM. A novel scFV candidate (Clone H8) to L1CAM was obtained by bio-panning of phage displaying human synthetic scFv fragments to human and mouse L1CAM proteins. H8 scFV was linked to IgD-IgG1 hinge, CD28 transmembrane domain, CD28 and ICOS co-stimulation domain, and CD3ζ domain, resulting in CX804 CAR-T. The efficacy of L1CAM CAR-T cells, CX804 showed correlation with the level of L1CAM in human ovarian and gastric cancer cells. CX804 exerted cytotoxicity toward 293T cells expressing human or mouse L1CAM protein. CX804 also reacted with L1CAM-positive ovarian SKOV3 cancer cell and gastric MKN-28 and AGS cancer cells and secreted T-cell activation cytokines, IFN-γ and TNF-α, in response to these cells. However, CX804 rarely lysed L1CAM-negative normal 293 cells and SNU-719 gastric cancer cells. Furthermore, L1CAM CAR-T cells dramatically lysed high L1CAM expressing patient derived cell (PDC) of gastric cancer compared with low L1CAM expressing PDC cell. Xenograft model of ovarian cancer was developed by intraperitoneal (IP) injecting SKOV3-Fluc cells into NOD/SCID or NSG mice. CAR-T cells were administrated via intravenous (IV) or IP route on 5 days after tumor inoculation. Administration of CX804 significantly decreased tumor burden and increased survival in mouse model of ovarian cancer. Route of administration significantly affected bio-distribution and antitumor effect of CX804 where antitumor activity of CX804 was only observed when CX804 were given IP, but not the IV route. Taken together, our results suggest that CX804 exerts potent and specific effect against L1CAM positive cancer cells in vitro and in vivo. Furthermore, we propose that newly established CAR-T cells targeting L1CAM facilitate therapy against L1CAM-positive ovarian and gastric cancer patients Citation Format: Xiumei Che, Un-Jung Yun, Seokwon Lee, Youngyoub Kim, Junshub Lee, Jina Chae, Jehee Suh, Eun-Ji Nam, Gun Min Kim, Hyoyoung Kim, Minkyu Jung. Development of a novel L1CAM-targeted CAR-T, CX804, and its therapeutic efficacy in ovarian and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1772.
Abstract 112: Multi-omics analysis of molecular landscape and heterogeneity in fetal adenocarcinoma of the lung
Authors: Wei Guo, Li Sun, Xiaoxi Chen, Haitao Zhou, Shi Yan, Gang Zhao, Haimeng Tang, Hua Bao, Xue Wu, Yang Shao, Lin Lin
Journal: Cancer Research (2023)

Abstract Background: Fetal adenocarcinoma of the lung (FLAC) is a rare form of lung adenocarcinoma and was divided into high-grade (H-FLAC) and low-grade (L-FLAC) subtypes. Until now, much of the knowledge regarding FLAC is from case reports or small case series and there was no comprehensive multi-omics study of FLAC. Methods: A total of 20 FLAC patients who underwent tumor resection were retrospectively recruited in this study. Three regions from each of the 20 tumor specimens and matched normal tissue specimens were collected. Whole-exome sequencing, targeted bisulfite sequencing and whole transcriptome sequencing were performed on multi-regional tumor samples and normal tissue samples. Results: We compared our FLAC cohort with a conventional East Asian-ancestry lung adenocarcinoma (LUAD) and revealed lower frequencies of altered driver genes on both somatic mutations and CNV levels, including EGFR, KRAS and ERRB2, in FLAC. Mutational signature analysis showed an enrichment of age-related mutational signatures in FLAC and tobacco-associated and defective DNA mismatch repair-related signatures were more enriched in H-FLAC and in L-FLAC, respectively. Significant differences between H-FLAC and L-FLAC were observed in the genomic and epigenomic landscape. In contrast, the transcriptomic landscape of H-FLAC closely dissembled L-FLAC by pathway enrichment analysis of differentially expressed genes. Furthermore, although genetic and epigenetic changes showed congruent evolutionary trajectories, the relationships between multi-level intratumor heterogeneity (ITH) were distinct in H-FLAC and L-FLAC. The genetic and transcriptional ITH showed a significant negative correlation in H-FLAC but a significant positive correlation in L-FLAC. Moreover, the lower genetic ITH was significantly related to a worse recurrence-free survival and overall survival in FLAC patients whereas lower methylation ITH H-FLAC patients tended to have better survival. Conclusions: In this study, we first depicted the multi-omics landscapes of this rare lung cancer type and compared the two subtypes in a multi-omics and heterogeneity aspect. Different levels of ITH showed different relationships with survival, and non-genetic ITH, instead of genetic ITH, may contribute to the prognosis in FLAC patients. Citation Format: Wei Guo, Li Sun, Xiaoxi Chen, Haitao Zhou, Shi Yan, Gang Zhao, Haimeng Tang, Hua Bao, Xue Wu, Yang Shao, Lin Lin. Multi-omics analysis of molecular landscape and heterogeneity in fetal adenocarcinoma of the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 112.
Abstract 2033: Assessment of human reference genomes on cancer somatic mutation detection in tumor-normal paired reference samples using whole genome short-read sequencing data
Authors: Chunlin Xiao, Valerie Schneider
Journal: Cancer Research (2023)

Abstract A typical cancer somatic mutation identification workflow involves using a standard human reference genome for aligning the sequencing reads and annotating the uncovered somatic variants. The completeness and the correctness of the reference genome, and the haplotype representations may all impact the sequencing read alignments and subsequent somatic variant identifications. However, the exact impacts of the underlying references being used on somatic mutation analysis has not been investigated. In this study, we selected 3 human reference genomes, including GRCh38, T2TCHM13, and a personalized genome (PG) that was derived from a normal cell line, and 12 tumor normal paired replicates of Illumina short read sequencing data for the HCC1395 breast cancer cell line and a matched normal cell line, and aim to illustrate and quantify the effects of the reference genomes on the accuracy of somatic SNV/SV mutation detection using various somatic variant callers. Our analysis shows that the use of a personalized haplotype-specific genome assembly, rather than an unrelated genome such as GRCh38 or T2TCHM13 as a reference, not only improves read alignments for short-read sequencing data but also ameliorates the detection accuracy of somatic SNVs and SVs. While most somatic mutation calls are identical or equivalent, we identify GRCh38 and T2TCHM13 specific somatic mutations that may need to be avoided for further pursuit of incorrect treatment options. We uncover novel somatic mutations only when personalized genome assembly is used as a reference, some of which overlap with genes involving with pathways related to cancer invasion and metastasis (e.g., CDH23, ST14 etc.). The predicted somatic SVs are found more precise. Such results may provide additional interventional target choices for patients, researchers or clinicians, and physicians to look into further for personalized patient care. Citation Format: Chunlin Xiao, Valerie Schneider. Assessment of human reference genomes on cancer somatic mutation detection in tumor-normal paired reference samples using whole genome short-read sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2033.
Abstract 1234: Tumor cell-intrinsic PD-L1 promotes epithelial-to-mesenchymal transition in non-small cell lung cancer in interferon-g-independent and dependent way
Authors: Hyein Jeong, Hyun Kyung Ahn, Sehui Kim, Yoon Kyung Jeon
Journal: Cancer Research (2023)

Abstract The immune checkpoint molecule programmed cell death-ligand 1 (PD-L1, CD274) suppresses immunity when the cell surface PD-L1 is engaged by programmed death-1 (PD-1) on antitumor immune cells. Although PD-L1 has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutic development. In this study, we showed that PD-L1 facilitates epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells by upregulating EMT transcription factors and mesenchymal markers, and downregulating epithelial marker. RNA-sequencing was performed on paired exogenously PD-L1-overexpressed A549 cells and wild-type cells, and PD-L1-depleted H460 cells and wild-type cells, and transcriptomic features associated with PD-L1 status were identified using Gene Set Enrichment Analysis (GSEA). In both the paired samples, PD-L1 expression was associated with EMT-related pathways. Subsequent in vitro experiment showed that exogenous overexpression of PD-L1 in A549 and H522 cells increased both mRNA and protein expression of Twist, Zeb1, Snail, Slug, Vimentin, Fibronectin, and N-Cadherin. Correspondingly, the transcription factors and mesenchymal markers were decreased in PD-L1-depleted H460 and H596 cells. Recombinant PD-1 treatment also increased the expression of EMT transcription factors and markers on A549 and H460 cells. Moreover, interferon-γ stimulation on tumor cells increased expression of EMT transcription factors and markers, which was suppressed by PD-L1-knockdown, suggesting that interferon-γ-induced PD-L1 contributes to EMT. Our findings suggest that PD-L1 facilitates NSCLC progression by promoting the EMT in interferon-γ-independent and dependent way, and this intrinsic PD-L1 function could be targeted for better clinical management of PD-L1-overexpressing NSCLCs. Citation Format: Hyein Jeong, Hyun Kyung Ahn, Sehui Kim, Yoon Kyung Jeon. Tumor cell-intrinsic PD-L1 promotes epithelial-to-mesenchymal transition in non-small cell lung cancer in interferon-g-independent and dependent way [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1234.
Abstract 5339: 4-Amino-<i>N</i>-phenylbenzamides as dual-targeted mEGFR and AURK inhibitors and anticancer agents
Authors: Brianne Rogers, Nicholas Rohde, Justin Mikitaroff, Joshua Matson, Samantha Satawa, Felix Amissah, Sonali Kurup
Journal: Cancer Research (2023)

Abstract Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors are rendered ineffective in NSCLC due to mutations within the enzyme binding sites and redundant signaling pathways. The mEGFR inhibitors were found to retain their anticancer effects in NSCLC cells if given concurrently with AURK inhibitors. Dual-targeted small molecules designed to inhibit both mEGFR and AURK could demonstrate improved anticancer effects compared to monotargeted mEGFR inhibitors. We conducted molecular modeling studies to determine if there were similarities between the kinase pockets of mEGFR and AURK that could be exploited to develop dual-targeted mEGFR and AURK inhibitors. An overlap was observed for the active and allosteric sites of the kinase pocket for mEGFR and AURK. A series of compounds were synthesized and evaluated against mEGFR, AURKA, and AURKB. We found the kinase inhibitory profile to vary significantly depending on the substitution pattern ranging from selective mEGFR inhibitors to dual mEGFR and AURK inhibitors. The 4-substituted amino-N-phenylbenzamides were identified as dual mEGFR/AURK inhibitors. Dual mEGFR/AURK inhibitors demonstrated varied modes of binding within mEGFR and AURK. The most potent dual mEGFR and AURK inhibitors displayed nanomolar inhibition of mEGFR and AURK, and single-digit micromolar inhibition of non-small cell lung cancer cells. Target compounds were further evaluated in a 96-kinase screening assay and demonstrated selectivity for target kinases. The synthesis, structure-activity relationship (SAR) analysis and anticancer effects will be presented and discussed. Citation Format: Brianne Rogers, Nicholas Rohde, Justin Mikitaroff, Joshua Matson, Samantha Satawa, Felix Amissah, Sonali Kurup. 4-Amino-N-phenylbenzamides as dual-targeted mEGFR and AURK inhibitors and anticancer agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5339.
Abstract 6202: 6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer
Authors: Nadiia Lypova, Lilibeth Lanceta, Susan Dougherty, Jason Chesney, Yoannis Imbert-Fernandez
Journal: Cancer Research (2023)

Abstract Activating mutations of epidermal growth factor receptor (mutEGFR) are established drivers of lung tumor development, aggressiveness, and resistance to targeted therapies. While targeting mutEGFR with small-molecule tyrosine kinase inhibitors (EGFR-TKIs) dramatically improved progression-free survival in patients with non-small cell lung cancers (NSCLCs), intrinsic or acquired resistance to TKI therapy limits the duration of an effective response to TKIs. Alteration in DNA damage response (DDR) plays a vital role in genomic stability and cancer progression and helps cells to escape apoptosis, limiting the efficacy of targeted therapies. Interestingly, lung cancer cells exposed to EGFR-TKIs demonstrate attenuated glycolytic flux - one of the major providers of precursors for de novo nucleotide synthesis. A key regulator of glycolysis is the enzyme 6-phosphofructo-2-kinase (PFKFB3). PFKFB3 synthesizes fructose 2,6-bisphosphate (F2,6BP), which is a potent allosteric activator of the glycolytic rate-limiting enzyme, 6-phosphofructo-1-kinase (PFK1). Accordingly, F2,6BP controls flux throughout the entire glycolytic pathway. In preliminary studies, we provide evidence that PFKFB3 plays multiple roles in regulating the efficacy of DDR in lung cancer cells exposed to EGFR-TKIs. We show that PFKFB3 is required for EGFR-driven glucose metabolism, which provides a list of intermediates utilized in nucleotide synthesis. PFKFB3 regulates the expression of ribonucleotide reductase small subunit M2 (RRM2) of the ribonucleotide reductase (RNR), which is important for de novo onsite synthesis of deoxynucleotide triphosphate (dNTP) during DNA replication and repair. Moreover, a PFKFB3 inhibitor, PFK-158, increases oxidative stress in mutEGFR lung cancer cell lines and, as a result, promotes DNA damage. Importantly, we found that PFKFB3 plays an important role in the chromatin binding of scaffold proteins regulating the assembly of DNA repair complex. Our studies suggest that PFKFB3 plays an important role in DDR and provide a clear rationale to propose the use of PFKFB3 inhibitors in combination with EGFR inhibitors to increase the efficiency and/or overcome resistance to EGFR-TKIs. Citation Format: Nadiia Lypova, Lilibeth Lanceta, Susan Dougherty, Jason Chesney, Yoannis Imbert-Fernandez. 6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6202.
Abstract 1404: A functional genetic polymorphism of mitochondrion-associated DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma
Authors: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang
Journal: Cancer Research (2023)

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide and may progress to nonalcoholic steatohepatitis (NASH). Although emerging evidence suggests that NASH would be an important driver of hepatocellular carcinoma (HCC), molecularly what drives the transition of NAFLD to NASH and then HCC has not been clearly defined. Since NASH is a mitochondrial disease, we aimed to determine genetic variants associated with mitochondrial dysfunction linked to NASH and NASH-related HCC. We performed an integrative genomics analysis by analyzing a large-scale genome-wide association study of the body fat distribution-related variants in 344,369 individuals from multiple ancestries. And we linked these results to the top 24 significant variants to NASH and NASH-related HCC in 1,009 individuals from the NCI-UMD cohort. We also performed the expression quantitative trait loci (eQTL) analysis on candidate variants. We analyzed the 3D genome architecture especially chromatin topology based on UCSC Genome Browser that influences the expression of candidate variants. As a result, we identified rs3747579-TT, an eQTL to a mitochondrial chaperone Hsp40, also known as DNAJA3 rather than a coding variant, as a risk allele linked to NASH-related HCC. HCC patients with rs3747579-TT variant had a poor prognosis compared to HCC patients with rs3747579-CT or CC variant. We confirmed that HCC with rs3747579-TT had a reduced expression of DNAJA3, encoding a protein that maintains mitochondrial homeostasis. Consistently, HCC patients with low DNAJA3 expression had a poor prognosis. We found a specific site based on chromatin topology that may influence rs3747579 to regulate the expression of DNAJA3. In summary, we identified rs3747579-TT as a functional polymorphic variant of DNAJA3 that may be responsible for the development of NASH and NASH-related HCC. Citation Format: Yuto Shiode, Ching-Wen Chang, Xin Wei Wang. A functional genetic polymorphism of mitochondrion-associated DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1404.